P Zeitler

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (15)52.26 Total impact

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    ABSTRACT: Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.
    Blood 12/2006; 108(9):3021-6. DOI:10.1182/blood-2006-04-017350 · 10.43 Impact Factor
  • P Zeitler, J Pahnke, A Marx
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    ABSTRACT: To investigate whether degrading proteases can be found in patent calvarial sutures. Sutural growth and fusion means replacement of the sutural connective tissue, rich in fibronectin and collagen type V, by expanding calvarial bone. Proliferation of one tissue into the border area of another implies the presence of enzymes able to degrade extracellular matrix (ECM). An important family of proteases is the matrix metalloproteinases (MMPs), as is the plasminogen/plasmin system. Expression of two MMPs with substrate specifity for fibronectin and collagen type V and of the plasminogen activator system was studied by immunohistochemistry in samples of human fetal calvariae (age range weeks 19-35 of gestation). In all cases, intense staining for MMPs, urokinase, and urokinase receptor was found in the sutural connective tissue and along the outer and inner borders of calvarial bone. Our findings suggest that degradation of sutural connective tissue takes place during sutural growth. This might facilitate proliferation of calvarial bone. Recently, it was shown that an important regulatory mechanism of sutural growth is apoptosis of osteoblasts in the osteogenic front. Intact fibronectin is known to prevent apoptosis of proliferating osteoblasts while fibronectin degradation induces their apoptosis.
    Histopathology 05/2004; 44(4):360-6. DOI:10.1111/j.1365-2559.2004.01854.x · 3.30 Impact Factor
  • Petra Zeitler, Jan Pahnke, Hartmut Collmann
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    ABSTRACT: In cranial sutural samples derived from five children with premature cranial suture fusion we have performed immunostaining for the urokinase plasminogen activator (uPA) and urokinase receptor (uPAR). We have found a strong reactivity for cell- or matrix-bound uPA and uPAR in the sutural connective tissue and associated with the osteoblasts and osteocytes lining the calvarial bone. The sutural tissue itself showed a banding with different intensity of urokinase and uPAR staining concerning connective tissue. It is proposed that the components of the plasminogen activating system are involved in tissue turnover of sutural tissue and in sutural growth.
    Orthodontics and Craniofacial Research 03/2002; 5(1):22-8. DOI:10.1034/j.1600-0544.2002.50101.x · 1.29 Impact Factor
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    ABSTRACT: Severe type I plasminogen deficiency has been recently linked to ligneous conjunctivitis, a rare and uncommon form of chronic conjunctivitis. In this study, eight unrelated ligneous conjunctivitis patients living in different parts of the world were examined. All affected subjects from which plasma was available displayed absent or markedly reduced plasminogen antigen and plasminogen functional activity. Molecular genetic studies of seven patients identified a Lys19-->Glu mutation in two boys in a homozygous state, and in two girls in a compound-heterozygous state in which the second plasminogen gene carried a missense (Arg134-->Lys) and a nonsense mutation (Cys133--> Stop), respectively. A fifth patient was shown to be homozygous for a frameshift mutation in plasminogen exon 14 (Gly565ins-G). In two unrelated subjects with ligneous conjunctivitis no mutations in the plasminogen gene were identified. Our results suggest that the Lys19-->Glu mutation is the most prevalent mutation in the plasminogen gene of patients with ligneous conjunctivitis.
    Thrombosis and Haemostasis 06/2001; 85(6):1004-10. · 5.76 Impact Factor
  • P Zeitler, A Thiede, H L Müller
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    ABSTRACT: In a prospective study, clotting parameters of 37 children and adolescents with insulin-dependent diabetes mellitus (type 1 diabetes) were compared with those of a healthy control group. In a longitudinal follow-up over two years we found no statistical difference for most of the coagulation parameters investigated, including single factor analysis and coagulation inhibitors. The duration of type 1 diabetes was of no influence on these parameters. The only difference we found between patients and healthy controls was an elevation of PAI-1 in diabetics: median for PAI-1: 2.12 IU/ml in diabetics (range 0.50-8.40 IU/ml) and 0.84 IU/ml in normal controls (range 0.50-1.78 IU/ml). This difference was of statistic significance (p < 0.002) and also found in newly diagnosed patients. During observation time, none of our patients developed thrombosis or signs of vascular disease. In conclusion, we could not confirm the development of a hyper-coagulable state in pediatric diabetics, as it is described for adults with type 1 diabetes mellitus.
    Experimental and Clinical Endocrinology & Diabetes 01/2001; 109(3):146-50. DOI:10.1055/s-2001-14837 · 1.76 Impact Factor
  • P Zeitler, J Pahnke, S Braitinger
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    ABSTRACT: Aim of this study was to evaluate the postnatal growth pattern of the sphenoid sinus. 83 cerebral MRI examinations of infants and children aged 5 months to 14 years were retrospectively reviewed for pneumatization and growth of sphenoid sinus. A continuous increase of pneumatization and growth of the sphenoid sinus was demonstrated between infancy and adolescence including considerable individual variations. Even in children less than two years old remarkable spatial extends of this sinus could be found in some cases. Diagnosis of an acute or chronical sinusitis in pediatric patients should alert the clinician to the possibility of a sphenoidal participation.
    Laryngo-Rhino-Otologie 10/2000; 79(9):526-31. DOI:10.1055/s-2000-6939 · 0.99 Impact Factor
  • J Kraft, W Lieb, P Zeitler, V Schuster
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    ABSTRACT: Ligneous conjunctivitis is a rare form of chronic recurrent pseudomembranous disease and may be associated with systemic membranous pathological changes. Recently ligneous conjunctivitis has been linked to severe type I plasminogen deficiency. We report on a patient with plasminogen deficiency and severe bilateral ligneous conjunctivitis. A new treatment approach and its outcome in this patient are described. We present the case of a 9-month-old Turkish girl with massive swelling of the eyelids and hard white pseudomembranes on both lids. The conjunctival smear was positive for Streptococcus pneumoniae. The clinical diagnosis was: ligneous conjunctivitis with superinfection. Histological investigation showed fibrin as major component of the pseudomembranes. The coagulation analyses revealed decreased plasminogen activity (<5%; normal 80-120%) and decreased plasminogen antigen (<0.4 mg/dl; normal 6-25 mg/dl). The failure of surgical therapy led to the attempt at treatment with intravenous lys-plasminogen. A significant improvement of the ocular symptoms occurred; stabilization with no recurrent pseudomembranes could be achieved for 6 months after treatment. The initial amelioration of symptoms in our patient after systemic replacement therapy confirms the etiological importance of plasminogen deficiency in the development of ligneous conjunctivitis. Curative treatment of ligneous conjunctivitis is still not available. However, intravenous application of plasminogen offers new possibilities in therapy, although long-term treatment seems necessary.
    Albrecht von Graæes Archiv für Ophthalmologie 10/2000; 238(9):797-800. DOI:10.1007/s004170000172 · 2.33 Impact Factor
  • P Zeitler, V Schuster
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    ABSTRACT: Urokinase-type plasminogen activator (u-PA) is one major activator of plasminogen. It is also involved in tissue remodelling, angiogenesis, cell migration, and tumour metastasis. In adults, increased u-PA levels have been identified in patients with chronic liver disease. No data exist for u-PA plasma levels in children. In the present study, u-PA plasma levels were measured by ELISA in 95 healthy children and adolescents aged 7 months to 17 years. We found a median value of 1.06 ng/ml u-PA (range 0.43-15.78 ng/ml), which is similar to that found in adults (2-20 ng/ml). No differences between males and females were recorded. In addition, we determined u-PA plasma levels of 16 patients with severe or mild type I plasminogen deficiency and found a median value of 1.06 ng/ml (range 0.69-7.7 ng/ml). CONCLUSION: Normal plasma u-PA values in healthy children and adults are virtually no different from those reported in adults.
    European Journal of Pediatrics 01/2000; 158 Suppl 3:S205-8. DOI:10.1007/PL00014360 · 1.98 Impact Factor
  • P Zeitler, N Meissner, H W Kreth
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    ABSTRACT: Factor XII deficiency can be associated with a thrombotic and VWF deficiency with a haemorrhagic clinical course. To study the potential influence of factor XII deficiency on bleeding tendency in patients suffering from VWD we retrospectively compared the clinical outcome of children with either an isolated factor XII deficiency, an isolated VWD, or a combination of both. Patients with the combined coagulation defect showed significantly fewer bleeding events when compared to patients with isolated VWD, although ristocetin cofactor activities were reduced to a comparable degree. As far as aPTT values are concerned, there were no significant differences among the three groups. Whether this combination of thrombophilic and haemorrhagic coagulation disorders is only coincidental or the result of an active modulation of one of the two counteracting coagulation factors is not known at present.
    Acta Paediatrica 12/1999; 88(11):1233-7. DOI:10.1080/080352599750030347 · 1.84 Impact Factor
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    ABSTRACT: Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 --> Glu/Arg513 --> His, Lys19 --> Glu/Arg216 --> His, and Lys19 --> Glu/Leu128 --> Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.
    Blood 05/1999; 93(10):3457-66. · 10.43 Impact Factor
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    ABSTRACT: On the basis of a questionnaire sent to the ophthalmology departments of hospitals throughout Germany, 10 patients with ligneous conjunctivitis or pseudomembranous disease, ranging in age from 1 to 71 years were identified. All 10 patients had severely reduced plasminogen levels. Genetic analysis revealed homozygous type I plasminogen deficiency (which had not previously been described in humans) in 7 patients and compound heterozygous plasminogen deficiency in 1 patient. Clear differentiation was not possible in 2 patients. Most of the parents had heterozygous plasminogen deficiency. None of the patients had experienced any episodes of thrombosis. Additionally, the following observations were made: 1) Levels of polymorphonuclear (PMN)-elastase protein were markedly elevated in 6 of 6 patients and 10 of 11 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XII deficiency was found in 3 of 6 patients tested. 3) C1-inhibitor was elevated in 2 of 4 patients, prekallikrein was elevated in 1 of 4 patients, and plasminogen activator inhibitor type 1 was elevated in 1 of 4 patients. Infusions of lys-plasminogen concentrate induced pronounced fibrinolytic activity as indicated by high levels of D-dimer, increases in plasmin-antiplasmin complex and decreases in polymorphonuclear elastase. C1-inhibitor, prekallikrein and PAI-1 normalized after repeated infusions of lys-plasminogen. In contrast to dysplasminogenemia, severe type I plasminogen deficiency might be seen as a problem of extravascular space, in particular of the mucous membranes, possibly triggered by mechanically induced or inflammatory lesions of the vessels supplying the tissue.
    Apmis 02/1999; 107(1):62-72. DOI:10.1111/j.1699-0463.1999.tb01527.x · 1.92 Impact Factor
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    ABSTRACT: Laboratory studies were performed on six female patients (ranging in age from 1 to 31 years) with ligneous conjunctivitis, which we regard as a systemic condition consisting of ligneous conjunctivitis and other pseudomembranous lesions. Plasminogen levels were severely reduced in all six patients; five patients were homozygous, and one patient was double heterozygous for type I plasminogen deficiency. Of family members tested, 11 of 12 parents and two of six siblings tested were diagnosed as heterozygous. No thrombotic episodes had occurred in any of the patients. Polymorphonuclear (PMN) elastase protein levels were markedly elevated in all, significantly more so in the homozygous patients (range 88 to 335 ng/mL; normal range, 20+/-10 ng/mL) than in the heterozygous patient (58 ng/mL). Of 11 parents examined, only 1 mother had normal PMN elastase (27 ng/mL, with plasminogen antigen 60% and plasminogen functional activity 86%), whereas values were moderately elevated (range 42 to 110 ng/mL) in the other 10 parents examined. After plasminogen substitution, PMN elastase levels consistently decreased but did not reach normal values. We interpret our findings as indicating that non-plasmin-induced fibrinolytic processes, possibly mediated via elastase, may be intensified in patients with plasminogen deficiency.
    Seminars in Thrombosis and Hemostasis 02/1998; 24(6):605-12. DOI:10.1055/s-2007-996061 · 3.69 Impact Factor
  • 10/1997; 11:20-20. DOI:10.1016/S0268-9499(97)80184-1
  • Pediatric Research 05/1997; 41(5). DOI:10.1203/00006450-199705000-00201 · 2.84 Impact Factor
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    ABSTRACT: Homozygous type I plasminogen (Plg) deficiency has not been described in human subjects so far. Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis of unknown etiology. Here we report for the first time on homozygous type I Plg deficiency in three unrelated female patients who suffered from ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes. The disease is caused by massive fibrin depositions within the "extravascular space" of mucous membranes because of absent clearance by plasmin. Infusions of albumin, fresh frozen plasma, or Lys-plasminogen (Lys-Plg) into two of the three patients revealed normal Plg activation capacity in these patients. The absence of fibrinolytic activity could therefore be shown to be due to Plg deficiency. Similar studies in the third patient have not been completed. In the two patients studied so far, infusions of Lys-Plg resulted in prompt and adequate Plg recovery with a short half-life and high amounts of plasmin-antiplasmin complexes and D-dimer. One patient additionally revealed an inherited partial factor XII deficiency. Functionally, this factor XII deficiency did not interfere with Plg activation. However, there may be a pathway of Plg activation in this patient via the prekallikrein C1-INH system.
    Seminars in Thrombosis and Hemostasis 02/1997; 23(3):259-69. DOI:10.1055/s-2007-996099 · 3.69 Impact Factor

Publication Stats

235 Citations
52.26 Total Impact Points

Institutions

  • 1998–2002
    • University of Wuerzburg
      • Department of Paediatrics
      Würzburg, Bavaria, Germany
  • 2001
    • University of Leipzig
      Leipzig, Saxony, Germany